Hereditary melanoma: Update on syndromes and management: Genetics of familial atypical multiple mole melanoma syndrome

Abstract

Malignant melanoma is considered the most lethal skin cancer if it is not detected and treated during its early stages. About 10% of melanoma patients report a family history of melanoma; however, individuals with features of true hereditary melanoma (ie, unilateral lineage, multigenerational, multiple primary lesions, and early onset of disease) are in fact quite rare. Although many new loci have been implicated in hereditary melanoma, CDKN2A mutations remain the most common. Familial melanoma in the presence of multiple atypical nevi should raise suspicion for a germline CDKN2A mutation. These patients have a high risk of developing multiple primary melanomas and internal organ malignancies, especially pancreatic cancer; therefore, a multidisciplinary approach is necessary in many cases. The value of dermoscopic examination and total body photography performed at regular intervals has been suggested by a number of studies, and should therefore be considered for these patients and their first-degree relatives. In addition, genetic counseling with the possibility of testing can be a valuable adjunct for familial melanoma patients. This must be performed with care, however, and only by qualified individuals trained in cancer risk analysis.

Keywords: CDK4; CDKN2A; FAMMM; familial melanoma syndromes; melanoma genetics; mixed cancer syndromes.

Figure 1. The familial atypical multiple mole-melanoma phenotype

(a) Clinically atypical moles frequently associated with FAMMM syndrome. (b) Pedigree of a FAMMM kindred showing multiple early onset cutaneous melanomas (proband and brother) and pancreatic cancer (PANC CA; mother). The patient and mother are carriers of a p16 mutation (m). (c) Patients with FAMMM syndrome (in particular those with germline CDKN2A mutations) are at risk for cutaneous melanoma, pancreatic cancer and neural systems tumors (melanoma-astrocytoma syndrome).

Figure 2. Pathways linked to FAMMM predisposition

CDKN2A is comprised of 4 exons- 1α, 1β, 2 and 3. Exons 1α, 2 and 3 encode for p16 while exons 1β, 2 and 3 encode for p14ARF (ARF). p16 inhibits CDK4, which, without p16, binds cyclin D (CYCD) and phosphorylates (P) the retinoblastoma protein (RB). This in turn releases E2F transcription factors, which induces G1 phase genes and triggers G1-S cell cycle transition. p14ARF inhibits HDM2, which normally ubiquitinates (Ub) p53 condemning it to destruction by the proteasome. Mutations in CDKN2A (CDKN2A*) leads to loss of p14ARF and p16 function (gray color) while mutations in CDK4 (CDK4*) renders CDK4 resistant to p16 inhibition thereby activating CDK4 activity (red color); non-mutated genes are shown in green.

Figure 3. Genetic counseling algorithm for FAMMM patients

Patients with a personal history of melanoma may be considered for genetic counseling if certain criteria from high and low incidence area are met. The United States and Australia would be considered high incidence areas while England and Greece would be considered low incidence areas. A genetic counselor would ascertain a 3-generation pedigree and discuss the likelihood of hereditary melanoma, the molecular genetics related to familial melanoma risk, testing options, costs, risks of discrimination and possible test results. If patient undergoes CDKN2A testing and a deleterious mutation is detected, intensive skin surveillance is recommended along with a referral to GI for discussion of pancreatic cancer screening. If testing is not pursued or if a normal or variant of unknown significance result is returned, the etiology of the familial pattern remains unknown. Given the family history, the patient is considered high risk and should undergo high level skin surveillance. Abbreviations, PC, pancreatic cancer; TBP, total body photography, CMM, cutaneous malignant melanoma.